Decreased and Heterogeneous Neutralizing Antibody Responses Against RBD of SARS-CoV-2 Variants After mRNA Vaccination

Abstract

The rapid spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) emerging variants raises concerns about their capacity to evade immune protection provided by natural infection or vaccination. The receptor-binding domain (RBD) of the viral spike protein is the major target of neutralizing antibodies, and viral variants accumulate mutations in this region. In this study, we determined the antibody neutralization capacity against the RBD of SARS-CoV-2 variants Alpha (B.1.1.7), Gamma (P.1), Epsilon (B.1.427), Kappa (B.1.617.1), and Delta (B.1.617.2) in a cohort of healthcare workers naturally infected or receiving COVID-19 mRNA vaccines from Moderna or Pfizer-BioNTech. We show that the five RBD variants displayed an augmented binding to ACE2 compared to the original Wuhan strain. The most significant increase was observed in variants Epsilon and Delta, containing mutation L452R. Using a flow cytometry cell-based assay, we found that SARS-CoV-2-infected subjects presented low levels of RBD-specific neutralizing antibodies against all variants analyzed, except Alpha. However, the neutralizing activity incremented considerably after a subsequent mRNA-vaccine dose, to levels significantly higher than those in naïve individuals receiving two vaccine doses. Importantly, we observed partially impaired neutralizing responses against most variants in fully vaccinated individuals. Variants Gamma and Kappa encompassing RBD E484K/Q mutations presented the highest neutralizing resistance. Furthermore, a wide heterogeneity in the magnitude of RBD-specific neutralizing responses against all tested SARS-CoV-2 variants following both mRNA vaccines was detected. Altogether, our findings provide important knowledge regarding SARS-CoV-2 vaccine-induced immunity, and should be very useful to guide future vaccination regimens and personalized vaccine approaches.

RBD-Based ELISA and Luminex Predict Anti-SARS-CoV-2 Surrogate-Neutralizing Activity in Two Longitudinal Cohorts of German and Spanish Health Care Workers

“…An additional advantage is that RBD from variants of concern (VoC) is relatively easy and rapid to produce. Thus, these antibody assays can be quickly adapted to measure plasma surrogate-neutralizing activity against RBD from newly emerging variants ( 46 ). nAbs binding the RBD are considered a serological correlate of protection; thus, once a cutoff is established, these simple antibody assays may allow for assessment of levels of protection to VoC ( 11 , 47 ).…”

Comparative Study of the Mutations Observed in the SARS-CoV-2 RBD Variants of Concern and Their Impact on the Interaction with the ACE2 Protein

“…73,74 The Delta variant is thought to be 40− 60% more transmissible than the Alpha variant and nearly twice as transmissible as the original Wuhan strain. 68,75 Although data suggest that vaccines are slightly less efficient in avoiding infection with the Delta form, 44,63 they are still quite effective in preventing serious disease. 76,77 The first verified Omicron infection was discovered in a sample collected on November 9, 2021.…”

“…Delta has the D614G mutation as well as a few other mutations not reported in other variants of concern . These include a L452R mutation on the RBD, which is expected to enhance infectivity and may help the virus escape immune cell destruction. − The Delta variant contains the T478K mutation also located on the RBD, which is thought to assist the virus avoid immune detection. − Finally, this variant of concern has a P681R mutation, which is linked to an increased ability to cause serious illnesses. , The Delta variant is thought to be 40–60% more transmissible than the Alpha variant and nearly twice as transmissible as the original Wuhan strain. , Although data suggest that vaccines are slightly less efficient in avoiding infection with the Delta form, , they are still quite effective in preventing serious disease. , …”

“…It is also assumed to be linked to worsening illness severity, but this is not clear . However, COVID-19 vaccinations and monoclonal antibody therapies have been reported to be still highly effective against it. − …”

Neutralization activity of IgG antibody in COVID‑19‑convalescent plasma against SARS-CoV-2 variants

“…They define three classes of SARS-CoV-2 variants 6 : the B.1.1.7 (alpha), B.1.351 (beta), P.1 (gamma), B.1.617.2 (delta) and B.1.1.529 (omicron) variants, which are classified as variants of concern (VOC), while B.1.617.1 (kappa) and R.1 variants are classified as variants of interest (VOI). Variant mutations in these viruses are associated with changes in the activity of receptor binding and reduced neutralization by antibodies [7][8][9] .…”